END Rheumatic Heart Disease

Acute rheumatic fever ( ARF ) is a preventable autoimmune disease triggered by group A streptococcal ( GAS ) infection that mostly affects children aged 5-to-14 years. Despite ARF largely eradicated in many high-income countries, ARF and its complication rheumatic heart disease ( RHD ) remain important causes of preventable suffering and death for Māori and Pacific New Zealanders. Gaps in knowledge of risk factors for ARF and RHD and its pathophysiology severely limit disease prevention and control.

END RHD includes a collaboration of researchers, universities, community organisations and is led by Dr Julie Bennett and Professor Michael Baker.

Our people

• Dr Julie Bennett
• Professor Michael Baker
• Dr Dianne Sika-Paotonu
• William Leung
• June Atkinson
• Jane Zhang
• Krishtika Mala PhD Fellow

Our projects

Vaccine Initiative to end Rheumatic Fever in Aotearoa New Zealand

Aim

Support vaccine development to help prevent rheumatic fever and rheumatic heart disease.

Funding

University of Auckland from June 2022 to January 2024.

Lead

Dr Julie Bennett
Email julie.bennett@otago.ac.nz

SCIP RHD

Subcutaneous infusions of benzathine penicillin G (BPG) for prevention of rheumatic heart disease

Background

There is an urgent need to improve penicillin formulations for all children living with ARF /RHD. Based on a randomised cross-over trial, we hypothesise that BPG could be repurposed as an 'implant' if given as a high-dose subcutaneous (SC) infusion of penicillin. By providing sustained penicillin concentrations for greater than 3 months, this approach would fulfil the ideal product characteristics for the next generation of long-acting penicillins. This 3-year multiphase program begins with a phase-I study, assessing the safety, tolerability and pharmacokinetics of SCIP in healthy adults (SCIP-I). An observational study of SCIP in children living with ARF will then be conducted (SCIP-II) to identify acceptability, barriers and benefits of SCIP RHD , both from consumer and health care provider perspectives.

Goal

We believe that 'better penicillins will lead to better hearts' for Māori and Pacific children at risk of heart disease and death due to ARF / RHD . Our vision is to re-purpose existing long-acting penicillin preparations as a novel 'implant'.

Aims

1. To define the pharmacokinetics, safety, tolerability and the effect of BMI of high-dose SC BPG given every 3 months in healthy, young adult volunteers (SCIP-I).
2. To demonstrate safety, tolerability and pharmaco-equivalence of high dose SC BPG in children/young adults with ARF currently receiving regular IM injections (SCIP-II).
3. To demonstrate acceptability of high dose SC BPG in Māori and Pacific children/young adults with ARF receiving regular IM injections (SCIP-IIa).

Funding

This project is funded by Cure Kids (Reference 7012).

Isolate study

Characteristics of S. pyogenes isolated prior to rheumatic fever diagnosis

Background

New Zealand has unique opportunity for rheumatic fever research, as we have high rates of ARF ; high levels of streptococcal testing as a result of a school based swabbing programme; established ability to link laboratory test results to subsequent disease; and the willingness of the community laboratory to store large numbers of specimens. This study would not be possible elsewhere in the world. Results from this study will provide critical missing knowledge about group A streptococcus isolated prior to the development of ARF . Such knowledge is vitally important to inform vaccine development.

Aims

1. Establish if group A streptococcal isolates detected prior to an ARF diagnosis differ from those isolates collected on hospital admission.
2. Establish if group A streptococcal isolates that cause ARF are different to those that are circulating in the population and those causing APSGN.
3. Establish whether differences between duplicate isolates are common and important.
4. Investigate immune responses of patients with ARF to group A streptococcal isolates.

Funding

This project is funded by the Health Research Council (HRC) of New Zealand (Reference 19/605).

Endgame

Developing an optimal strategy for the rheumatic fever endgame

Background

Acute rheumatic fever ( ARF ) and its serious complication rheumatic heart disease ( RHD ) produce large ethnic health inequities and remain important causes of preventable suffering and death for Māori and Pacific New Zealanders. There is a lack of agreement about the best mix of interventions to prevent ARF and reduce the health impact of RHD . This research will use a combined economic and epidemiological model to assess which interventions produce the greatest health gains for the same health resources. It will compare a range of interventions at the primordial (e.g. income, housing), primary (e.g. sore throat and skin infection treatment, vaccination), secondary (e.g. improved ARF diagnosis, antibiotic prophylaxis) and tertiary levels (e.g. better access to medical and surgical treatment of RHD ). New Zealand is investing significant resources in ARF and RHD prevention and control. This research will help ensure we achieve the best possible value for Māori and Pacific children.

Goal

Our goal is to support the design of an optimised, evidence-informed strategy that will contribute to the 'endgame' for ARF and RHD in New Zealand.

Aims

1. To construct an economic-epidemiological model of the natural history of ARF and RHD in New Zealand.
2. To use this model to estimate the incremental cost-effectiveness of a full range of plausible health sector interventions at the primary, secondary and tertiary prevention levels.
3. To investigate the feasibility of economic assessment of primordial prevention for ARF and RHD .

Design

In summary, this study will build an economic-epidemiological model of ARF / RHD , incorporating natural history, using (largely New Zealand) data on disease progression probabilities and the effectiveness of interventions. It will model at the population level the total costs and health outcomes from each of the intervention scenarios, then present the incremental costs and outcomes compared with the status quo. This model will estimate the incremental cost-effectiveness of a full range of plausible interventions across the ARF / RHD causal pathway. It will also consider the feasibility of economic evaluation of primordial interventions for reducing the disease burden. An international advisory committee composed of experts in ARF / RHD and economic evaluation will guide this research. The proposed optimal prevention strategy will be refined through discussions with reference groups representing the views or end-users and affected communities.

This project is funded by the Health Research Council (HRC) of New Zealand (Reference 18/079).

Understanding Group A Streptococcus ( GAS ) pharyngitis and skin infections as causes of rheumatic fever

Background

Acute rheumatic fever ( ARF ) is an autoimmune disease that may follow untreated GAS pharyngitis and untreated GAS skin infections, in susceptible children. Disease manifestations include inflammation in the joints, heart, central nervous system and skin. In an estimated 60% of cases, carditis progresses to chronic rheumatic heart disease ( RHD ) with permanent heart valve damage. Unless treated with intramuscular injections of benzathine penicillin G every 28 days, ARF patients are likely to suffer worsening cardiac damage and an increasing chance of early death.

ARF is now rarely seen in high-income countries, with the exception of New Zealand and Australia. There are large and widening ethnic disparities in ARF rates in New Zealand. ARF incidence peaks in children aged 4-15 years. The rate of new cases of ARF notified in 2016 for Maori 5-to-12-year-olds was 23.4 per 100,000 and for Pacific 5-to-12-year-olds was 62.9 per 100,000, many times higher than the rates for European/Others.

A major challenge for treating GAS pharyngitis, or mounting interventions amongst populations at high-risk of developing ARF , is that significant numbers of children naturally carry GAS in their throats without evidence of infection or any autoimmune sequelae. This study will serologically confirm GAS pharyngitis to differentiate between children with true pharyngitis, who are considered at risk of progressing to ARF , from those that are GAS carriers. The study will also investigate the role of GAS skin infections and potential risk factors associated with GAS pharyngitis and skin infections.

Aims

1. Determine the incidence and distribution of GAS pharyngitis (serologically confirmed) amongst children presenting with a sore throat.
2. Determine the incidence of GAS positive skin infections amongst children presenting with a skin infection and the serological response to these infections.
3. Compare the GAS emm types associated with GAS pharyngitis and skin infections to those associated with the GAS carrier date, ARF and well controls.
4. Identify epidemiological risk factors for GAS pharyngitis and skin infections and assess their potential as modifiable risk factors for these infections and ARF .
5. Assess the contribution of viral infection to presumed GAS pharyngitis seen in primary care.
6. Measure the persistence of GAS antibodies (and potentially GAS colonisation) six months following the initial sampling.
7. To determine age-specific upper level of normal (ULN) values of ASO and ADB titers in children.
8. To establish carriage rates of GAS in asymptomatic children.

Funding

This is a Health Research Council (HRC) funded project (Reference 16/005).

Risk factors for acute rheumatic fever – case-control study

Background

Acute rheumatic fever ( ARF ) and its sequela, rheumatic heart disease ( RHD ), have largely disappeared from high-income countries. However, in New Zealand, rates remain unacceptably high in indigenous Māori and Pacific populations.

Goal

The goal of this study is to identify potentially modifiable risk factors for ARF to support effective disease prevention policies and programmes.

Aims

1. Identify potentially modifiable environmental risk factors for ARF , notably household crowding and bed-sharing, poor housing conditions, and environmental tobacco smoke.
2. Establish whether access to healthcare, including sore throat treatment and related health literacy, is protective for ARF .
3. Establish whether current or recent skin infection is associated with an increased risk of ARF .
4. Establish whether poor oral health is associated with an increased risk of ARF .
5. Identify potentially modifiable host and nutritional factors for ARF , such as vitamin D deficiency, anaemia and high consumption of sugar-sweetened beverages.
6. Contribute to identifying immunological factors associated with an increased risk of ARF .
7. Establish whether specific GAS organisms are associated with ARF .

Funding

This is a Health Research Council (HRC) funded project (Reference 13/959).

Student projects

• Krishtika Mala (PhD) Treatment and interventions for group A streptococcal skin infections
• Jane Oliver (PhD, complete) Oliver, J. (2018). Acute rheumatic fever and group A Streptococcus in New Zealand: A descriptive epidemiological study (PhD). University of Otago, Dunedin, New Zealand.
  http://hdl.handle.net/10523/8266
• Sally Thomas (MPH, complete) Group A Streptococcus skin infection in New Zealand and its association with Acute Rheumatic Fever: A descriptive epidemiological study.

Research impact

Publications and Reports

• Enkel, S. L., Kado, J., Hla, T. K., Salman, S., Bennett, J., Anderson, A., … Manning, L. (2023). Qualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies. PLoS ONE, 18(4), e0285037. doi: 10.1371/journal.pone.0285037
• Likely rise in invasive strep infections in NZ requires a strategy. Julie Bennett, Nikki Moreland, Johanna Birrell, Rachel Webb, Amanda Kvalsvig, Sally Roberts, Michael Baker. The Briefing, 23 March 2023
• Rentta, N. N., Bennett, J., Leung, W., Webb, R., Jack, S., Harwood, M., Baker, M. G., … Wilson, N. (2022). Medical treatment for rheumatic heart disease: A narrative review. Heart, Lung & Circulation. Advance online publication. doi: 10.1016/j.hlc.2022.07.013.
• Baker, M. G., Gurney, J., Moreland, N. J., Bennett, J., Oliver, J., Williamson, D. A., Pierse, N., … Merriman, T. R., … Edwards, R., … Thomson, W. M., Zhang, J., & Lennon, D. (2022). Risk factors for acute rheumatic fever: A case-control study. Lancet Regional Health: Western Pacific. Advance online publication.
• Bennett, J. and M. Baker (2022). Skin infections confirmed as a cause of rheumatic fever www.labonline.com.au.
• Whitcombe, A. L., R. McGregor, J. Bennett, J. K. Gurney, D. A. Williamson, M. G. Baker and N. J. Moreland (2022). "Increased breadth of Group A Streptococcus antibody responses in children with Acute Rheumatic Fever compared to precursor pharyngitis and skin infections." J Infect Dis.
• Oliver, J., Bennett, J., Thomas, S., Zhang, J., Pierse, N., Moreland, N. J., Williamson, D. A., Jack, S., & Baker, M. (2021). Preceding group A streptococcus skin and throat infections are individually associated with acute rheumatic fever: Evidence from New Zealand. BMJ Global Health, 6, e007038.
  doi: 10.1136/bmjgh-2021-007038
• Bennett, J., Moreland, N. J., Williamson, D. A., Carapetis, J., Crane, J., Whitcombe, A. L., Jack, S., … Baker, M. G. (2021). Comparison of group A streptococcal titres in healthy children and those with pharyngitis and skin infections. Journal of Infection. Advance online publication.
  doi: 10.1016/j.jinf.2021.10.014
• Ralph, A. P., Webb, R., Moreland, N. J., McGregor, R., Bosco, A., Broadhurst, D., … Bennett, J., … Carapetis, J. R. (2021). Searching for a technology-driven acute rheumatic fever test: The START study protocol. BMJ Open, 11(9), e053720.
  doi: 10.1136/bmjopen-2021-053720
• Bennett, J., Anderson, A., 'Ofanoa, M., Anderson, P., Baker, M. G., Brown, R., … Eggleton, K., Harwood, M., … Malcolm, J., … Sika-Paotonu, D., … Wilson, N. (2021). Acute rheumatic fever: A preventable, inequitable disease: A call for action. New Zealand Medical Journal, 134(1535), 93-95.
  https://www.nzma.org.nz/journal
• Bennett, J., Rentta, N., Leung, W., Anderson, A., Oliver, J., Wyber, R., Harwood, M., … Baker, M. G. (2021). Structured review of primary interventions to reduce group A streptococcal infections, acute rheumatic fever and rheumatic heart disease. Journal of Paediatrics & Child Health. Advance online publication.
  doi: 10.1111/jpc.15514
• Bennett, J., Rentta, N. N., Leung, W., Atkinson, J., Wilson, N., Webb, R., & Baker, M. G. (2021). Early diagnosis of acute rheumatic fever and rheumatic heart disease as part of a secondary prevention strategy: Narrative review. Journal of Paediatrics & Child Health. Advance online publication.
  doi: 10.1111/jpc.15664
• Cannon, J. W., Bennett, J., Baker, M. G., & Carapetis, J. R. (2021). Time to address the neglected burden of group A Streptococcus. Medical Journal of Australia, 215(2), 94-94.e1.
  doi: 10.5694/mja2.51149
• Oliver, J., Robertson, O., Zhang, J., Marsters, B. L., Sika-Paotonu, D., Jack, S., Bennett, J., Williamson, D. A., … Pierse, N., & Baker, M. G. (2021). Early release-ethnically disparate disease progression and outcomes among acute rheumatic fever patients in New Zealand, 1989–2015. Emerging Infectious Diseases, 27(7), 1893-1901.
  doi: 10.3201/eid2707.203045
• Thomas, S., Bennett, J., Jack, S., Oliver, J., Purdie, G., Upton, A., & Baker, M. G. (2021). Descriptive analysis of group A Streptococcus in skin swabs and acute rheumatic fever, Auckland, New Zealand, 2010–2016. Lancet Regional Health: Western Pacific, 8, 100101.
  doi: 10.1016/j.lanwpc.2021.100101
• McGregor, R., Whitcombe, A. L., Sheen, C. R., Dickson, J. M., Day, C. L., Carlton, L. H., … Bennett, J., Baker, M. G., … Moreland, N. J. (2020). Collaborative networks enable the rapid establishment of serological assays for SARS-CoV-2 during nationwide lockdown in New Zealand. PeerJ, 8, e9863.
  doi: 10.7717/peerj.9863
• Cannon, J., Zhung, J., Bennett, J., Moreland, N. J., Baker, M. G., Geelhoed, E., … Jack, S. (2020). The economic and health burden of disease caused by Group A Streptococcus in New Zealand. International Journal of Infectious Diseases. Advance online publication.
  doi: 10.1016/j.ijid.2020.11.193
• Bennett, J., Moreland, N. J., Oliver, J., Crane, J., Williamson, D. A., Sika-Paotonu, D., … Baker, M. G. (2019). Understanding group A streptococcal pharyngitis and skin infections as causes of rheumatic fever: Protocol for a prospective disease incidence study. BMC Infectious Diseases, 19, 633.
  doi: 10.1186/s12879-019-4126-9
• Baker MG, Gurney J, Oliver J, et al. Risk Factors for Acute Rheumatic Fever: Literature Review and Protocol for a Case-Control Study in New Zealand. Int J Environ Res Public Health. 2019;16(22):4515. Published 2019 Nov 15.
  doi:10.3390/ijerph16224515
• Cannon JW, Jack S, Wu Y, Zhang J, Baker MG, Geelhoed E, Fraser J, Carapetis JR. An economic case for a vaccine to prevent group A streptococcus skin infections. Vaccine, 2018; 36: 6968-78.
  doi: 10.1016/j.vaccine.2018.10.001
• Oliver J, Pierse N, Williamson DA, Baker MG. Estimating the likely true changes in rheumatic fever incidence using two data sources. Epidemiology and Infection. 2018;146(2):265-75.
• Oliver J, Malliya Wadu E, Pierse N, Moreland NJ, Williamson DA, Baker MG. Group A Streptococcus pharyngitis and pharyngeal carriage: A meta-analysis. PLoS neglected tropical diseases. 2018 Mar;12(3):e0006335. PubMed PMID: 29554121. Pubmed Central PMCID: 5875889.
• Oliver J, Foster T, Williamson DA, Pierse N, Baker MG. Using preceding hospital admissions to identify children at risk of developing acute rheumatic fever. J Paediatr Child Health. 2018 May;54: 499-505. PubMed PMID: 29168244.
• Oliver J, Foster T, Kvalsvig A, Williamson DA, Baker MG, Pierse N. Risk of rehospitalisation and death for vulnerable New Zealand children. Arch Dis Child. 2018; 103: 327-34. PubMed PMID: 28735258.
• Jack SJ, Williamson DA, Galloway Y, Pierse N, Zhang J, Oliver J, Milne RJ, Mackereth G, Jackson CM, Steer AC, Carapetis JR, Baker MG. Primary prevention of rheumatic fever in the 21st century: evaluation of a national programme. Int J Epidemiol. 2018 Jul 27. PubMed PMID: 30060070.
• Doyle H, Pierse N, Tiatia R, Williamson D, Baker MG, Crane J. The effect of the oral probiotic Streptococcus salivarius (K12) on Group A streptococcus pharyngitis: a pragmatic trial in schools. Pediatr Infect Dis J. 2017 Nov 15.
  doi: 10.1097/INF.0000000000001847.[Epub ahead of print].
• Oliver JR, Pierse N, Stefanogiannis N, Jackson C, Baker MG. Acute rheumatic fever and exposure to poor housing conditions in New Zealand: A descriptive study. J Paediatrics Child Health. 2017, 53:358-64.
• Gurney JK, Stanley J, Baker MG, Wilson NJ, Sarfati D. Estimating the risk of acute rheumatic fever in New Zealand by age, ethnicity and deprivation" in its current form for publication in Epidemiology and Infection. Epidemiol Infect 2016 Jun 17:1-0.
• Jack S, Williamson D, Baker MG, Galloway Y, Pierse N, Milne R, Mackereth G, Zhang J, Oliver J. Interim Evaluation of the Sore Throat Component of the Rheumatic Fever Prevention Programme – Quantitative Findings. The Institute of Environmental Science and Research Ltd. Porirua, New Zealand; 2015
• Williamson DA, Smeesters PR, Steer AC, Steemson JD, Ng AC, Proft T, Fraser JD, Baker MG, Morgan J, Carter PE, Moreland NJ. M-protein analysis of Streptococcus pyogenes isolates associated with acute rheumatic fever in New Zealand. J Clin Micro. 2015 Nov 1;53(11):3618-20.
• Williamson DA, Morgan J, Fraser JD, Moreland NJ, Proft T, Mackereth G, Lennon D, Baker MG, Carter PE. Increasing incidence of invasive group A streptococcus disease in New Zealand, 2002 – 2012: A national population-based study. J Infect 2015;70:127-34.
• Oliver J, Baker MG, Pierse N, Carapetis J. Comparison of approaches to rheumatic fever surveillance across Organisation for Economic Co‐operation and Development countries. Journal of paediatrics and child health. 2015 Nov 1;51(11):1071-7.
• Oliver J, Pierse N, Baker MG. Estimating rheumatic fever incidence in New Zealand using multiple data sources. Epidemiol Infect 2015; 143: 167-177.
• Moreland NJ, Waddington CS, Williamson DA, Sriskandan S, Smeesters PR, Proft T, Steer AC, Walker MJ, Baker EN, Baker MG, Lennon D, Dunbar R, Carapetis J, Fraser JD. Working towards a Group A Streptococcal vaccine: Report of a collaborative Trans-Tasman workshop. Vaccine 2014.
• Oliver J, Pierse N, Baker MG. Improving rheumatic fever surveillance in New Zealand: Results of a surveillance sector review. BMC Public Health 2014, 14: 528.
• Williamson DA, Moreland NJ, Carter P, Upton A, Morgan J, Proft T, Lennon D, Baker MG, Dunbar R, Fraser JD. Molecular epidemiology of group A streptococcus from pharyngeal isolates in Auckland. NZ Med J 2013, 127: 55-60.
• Jaine R, Baker M, Venugopal K. Acute rheumatic fever associated with household crowding in a developed country. Pediatr Infect Dis J 2011; 30: 315-9.
• Jaine R, Baker M, Venugopal K. Epidemiology of acute rheumatic fever in New Zealand 1996-2005. Paediatrics and child health 2008;44:564-71.